(2R,3R)-2-(3-Carbamimidoyl-benzyl)-3-[4-(1-oxy-pyridin-4-yl)benzoylamino]-butyric acid methyl ester, (CAS number 193153-04-7) has the International Nonproprietary Name otamixaban and shows the structure illustrated in Formula I:

(2R,3R)-2-(3-Carbamimidoyl-benzyl)-3-[4-(1-oxy-pyridin-4-yl)benzoylamino]-butyric acid methyl ester (Otamixaban, Formula I) use in the preparation of a medicament for treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of Factor Xa has been disclosed in WO97/24118.
Factor Xa is the penultimate enzyme in the coagulation cascade. Factor Xa (fXa) is a critical serine protease situated at the confluence of the intrinsic and extrinsic pathways of the blood coagulation cascade. FXa catalyses the conversion of prothrombin to thrombin via the prothrombinase complex. Its singular role in thrombin generation, coupled with its potentiating effects on clot formation render it an attractive target for therapeutic intervention.
Both free factor Xa and factor Xa assembled in the prothrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) are inhibited by Otamixaban. Factor Xa inhibition is obtained by direct complex formation between the inhibitor and the enzyme and is therefore independent of the plasma co-factor antithrombin III. Effective factor Xa inhibition is achieved by administering the compound either by continuous intravenous infusion, bolus intravenous administration or any other parenteral route such that it achieves the desired effect of preventing the factor Xa induced formation of thrombin from prothrombin. In vivo experiments have demonstrated that Otamixaban is highly efficacious in rodent, canine and porcine models of thrombosis. In addition, recent clinical findings indicate that Otamixaban is efficacious, safe and well tolerated in humans and therefore has considerable potential for the treatment of acute coronary syndrome (K. R. Guertin and Yong-Mi Choi; 2007; Current Medicinal Chemistry, Vol. 14, No. 23; p. 2471-2481). Clinical findings in a dose-ranging clinical trial indicate that Otamixaban reduced prothrombin fragments 1+2 significantly more than unfractionated heparin at the highest dose regimen (Cohen et al., Circulation, Vol. 115, No. 20, May 2007, pages 2642-2651), but said clinical findings do not show data in comparison of age or renal impairment. Further clinical trials demonstrated that otamixaban induces dose-dependent, rapid direct factor Xa inhibition in patients with stable coronary artery disease who are taking their usual comedication, some of whom have mild renal impairment (Hinder et al., Clinical Pharmacology and Therapeutics, Vol. 80, No. 6, 2006, pages 691-702).
Acute coronary syndromes (ACS) are characterised by an imbalance between myocardial oxygen supply and demand. The most common cause is the reduced myocardial perfusion that results from coronary artery narrowing caused by a thrombus that has developed on a disrupted atherosclerotic plaque. Within the diagnosis of ACS two major subtypes can be distinguished that are non-ST elevation myocardial infarction (NSTE-ACS) and ST-elevation myocardial infarction (STE-MI). NSTE-ACS corresponds to a partial thrombotic occlusion of a coronary vessel with more or less pronounced ischemia. The main aim of treatment for these conditions is to prevent a sudden total occlusion of the arteries. STE-MI is characterised by a sudden total thrombotic occlusion of a coronary vessel resulting in ischemia of the heart. It needs to be treated urgently, within the initial 6-12 hours, and preferably 2 hours following the diagnosis. The goal is to restore patency (blood flow) of the occluded vessel.
Risk scores have been developed that regroup markers of the acute thrombotic process and other markers to identify patients with high-risk for total occlusion of vessels. In addition to the estimation of the risk, the assessment of the cardiac biomarker of necrosis, especially the cardiac troponins, are performed in order to select the treatment strategy of choice. It has been demonstrated during the last years that patients with moderate-to-high risk NSTE-ACS benefit from an early invasive strategy, where patients are brought early to a catheter lab (by the next day, or two) for angiography followed by a percutaneous coronary intervention (PCI). In recent US treatment guidelines for NSTE-ACS patients an invasive strategy is recommended for moderate-to-high risk patients while for lower risk patients a conservative strategy is preferred. However, timely access to invasive treatment is often more important for the decision than risk assessment. Furthermore, elderly and fragile patients are often not treated by invasive procedures due to increased risk for bleeding.
In all NSTE-ACS patients (with invasive or conservative strategy) a standard medical therapy is indicated including aspirin, clopidogrel and anticoagulant therapy. It appears beneficial to add an intravenous GPIIb/IIIa inhibitor, if an invasive strategy is planned in high-risk patients.
The primary discussions in medical literature today is focused on the moderate-to-high-risk NSTE-ACS patients, who are scheduled to undergo an early (≦48-72 h) diagnostic catheterization and coronary intervention. Aspirin, clopidogrel, GP IIb/IIIa inhibitors (including eptifibatide and abciximab), unfractionated heparin, bivalirudin, enoxaparin, fondaparinux are all recommended in the most recent guidelines indicating their recognition as standard of care for patients with moderate-to-high-risk NSTE-ACS.
Use of such a multi-tiered combination pharmacologic approach, however, has not been formally investigated and may result in increased risk of bleeding complications, greater complexity of treatment and increased costs. Further the presently used combination therapy of heparin and GP IIb/IIIa inhibitor is efficacious but causes bleeding in NSTE-ACS patients receiving dual oral antiplatelet therapy with aspirin and clopidogrel. Thus, the optimal anti-thrombotic regimen for moderate-to-high-risk for NSTE-ACS remains to be not found yet.
Further in the treatment of patients showing non-ST elevation myocardial infarction it is necessary that patients, who are elderly and/or show renal insufficiency (in the following NSTE-ACS risk patients) need a dose adjustment to avoid overdosing and bleeding. NSTE-ACS risk patients often show reduced compatibility to the used medicaments and have a higher risk of bleeding. Thus, NSTE-ACS risk patients have to be carefully adapted to the used anticoagulant therapy. Such an adaption is highly risky and could easily lead to a higher death rate and higher rate of myocardial infarction, because overdosing could not be avoided so easily.
It is an object of the present invention to find a medical treatment, which does not have the disadvantages mentioned and provides a reduction of death and/or myocardial infarction while retaining at least equal bleeding rates compared to standard therapy, in NSTE-ACS risk patients planned to undergo invasive management.
It has now unexpectedly been found that otamixaban offers improved management of NSTE-ACS risk patients. Unexpectedly, NSTE-ACS risk patients do not need a further adaption of their dosage regimen when treated with otamixaban. NSTE-ACS risk patients can be treated as the normal population having a dosage regimen which is solely weight-adjusted. Further patient safety is increased because the risk of a wrong dosage regimen does not occur. There is no need anymore for a different treatment between the normal patient and the NSTE-ACS risk patient. This is especially beneficial for elderly patients. There is also no need for dose adjustment of patients showing renal impairment (beyond weight-adjustment as in normal population) and this is especially beneficial in renal insufficient and severe renal insufficient patients. Further advantages of otamixaban are short initial half-life time, and mainly gastrointestinal excretion and a predictable relationship between pharmocokinetic and pharmacodynamic.